SE463260B - acetophenone - Google Patents

Description

CF 3 CH 2 O-A wherein A is -SO 2 CF 3 or an alkali metal, to provide a compound of formula CF 3 CH 2 O x O 10 OCH 2 CF 3 (2) acetylation in the presence of a Lewis acid catalyst to provide the substituted acetophenone of the present invention of formula 20 In (3) alternatively (a) chlorination of the substituted acetophenone to form the corresponding α, α-dichloroacetophenone and 30 b) adding a buffering base and further chlorination to provide u, a, or (c) reacting the substituted acetophenone with hypochlorite to form the corresponding benzoic acid and (d) reacting the acid with an inorganic acid. to provide the acid chloride 25 O than CF 3 CH 2 O 30 * and cr and then (4) reacting the product of step 3 (b) or step 3 (d) alternatively with 2- (aminomethyl) piperidine to form the desired the product in one step or with 2- (aminomethyl) pyridine, then reduction to form the desired product, optionally as the free base. The procedure comprising steps (1), (1) - (2); (3) (a); (3) (c); (1), (2) and (3) (c) $ (3) (b); (3) (a) and (3) (b); and (4) above constitute separate aspects of the overall invention as well as the intermediates CF 3 CH 2 O CB OCH 2 CF 3 wherein B is selected from -CH 3, -CHCl 2 and CCl 3.

The overall process of the present invention follows the scheme of the reaction: 4 »6 3 '3 s O II ocazcæc-'B cF3cH2o ccn3 ... à - z ä»' O (1) (2) (3) (a) ICIJ h) '(3) (c) cr- * Bcnzo ccci13 cf-3cH2o_ ccnclz Q 3 (b) O 2 \ øca2cr3 f I_V_ GCHZCPB <4) Q 0 fi II cF3cu2o cc1 cF3cn2o COH E gas (4) VI and H CF VII ocnzcs-B ___ 2 3 In the first step of the process, A is suitably -SO 2 CF 3 when X is OH and the reactants are heated together in a solvent such as acetone or N, N -dimethylformamide, and in the presence of a base, preferably a weak base, such as an alkali metal carbonate, t GX potassium or sodium fl carbonate. When X is Br, the 1A-dibromobenzene I is reacted with the 2,2,2- -trifluoroethoxide ion in a strongly polar solvent mixture at a temperature of up to the reflux temperature of the solution in the presence of copper (I) or copper (II) ion to give the desired product II in good yield. 2,2,2-trifluoroethoxide ion - is obtained from the corresponding alcohol by reaction with a strong base, such as sodium hydroxide or preferably sodium hydride. Suitable solvent mixtures include dimethyl sulfoxide, N, N-dimethylacetamide and preferably N, N-dimethylformamide, each with about 10-50% and preferably about 20% 2,2,2-trifluoroethanol.

Copper (I) ion is provided, for example, with a copper (I) halide, such as copper (I) iodide or copper (I) bromide. Copper (II) ion is produced, for example, by copper (II) bromide, copper (II) sulphate or copper (II) acetate.

In step (2), the 1,4-bis (2,2,2-trifluoroethoxy) benzene (II) prepared in that first step is acetylated by reaction under mild conditions with an acetylating agent, such as acetyl chloride or acetic anhydride, in the presence of of a Lewis acid catalyst, such as tin chloride, ferric chloride or preferably aluminum chloride. The acetylation is carried out in a suitable inert solvent such as a chlorinated hydrocarbon such as dichloromethane, trichlorethylene or 1,2-dichloroethane, diethyl ether, tetrahydrofuran and the like. Unexpectedly, this reaction produces high yields of the desired acetophenone (III).

Reaction step (3) (a) is a simple chlorination of intermediate III in a suitable solvent, such as ethyl acetate, a chlorinated hydrocarbon or preferably in acetic acid solution. This reaction is carried out at a moderate temperature, preferably 50-60 ° C.

The product IV can be isolated if desired or can, the chlorination is continued as in step (3) (b) to give the intermediate V by the addition of a buffer. means (eg an acetate salt, such as sodium acetate), and raising the temperature slightly, for example to 80-110 ° C, with continued chlorination. The reaction in step (3) (c) is most conveniently carried out by addition of the acetophenone III to a cold solution of an alkali metal or alkaline earth metal I hydroxide (such as sodium hydroxide, potassium hydroxide or calcium hydroxide), which has been saturated with chlorine to pH 7 (which forms the corresponding hypochlorite). The reaction is then facilitated by heating. A very high yield of the desired 2,5-bie- (2,2,2-trifluoroethoxy) benzoic acid VI is obtained.

In step (3) (d), the acid is converted to the corresponding acyl chloride by reaction with an inorganic acid chloride, such as thionyl chloride, phosphorus trichloride or phosphorus pentachloride (preferably phosphorus trichloride) at reflux with or without a suitable inert solvent, such as benzene or toluene or a halogenated hydrogen halide.

Step (4) of the process may be carried out directly from the saturated diamine-2- (aminomethyl) piperidine or indirectly from the unreduced diamine-2- (aminomethyl) pyridine; Thus, 2-aminomethylpiperidine may be reacted with the trichloroacetophenone product from step (3) (b) or the compound 2-aminomethylpyridine may be reacted with the trichloroacetophenone product V from step (3) (b). In each case, the reaction proceeds easily without external heating in an inert solvent such as toluene, benzene, isopropyl alcohol, cyclohexane and the like. The reaction proceeds particularly easily and in high yields when the unreduced diamine is reacted in a mixture of toluene and cyclohexane.

When the final step of the process is carried out starting from the acid chloride product VII in step (3) (d), it is also carried out directly from 2- (aminomethyl) -piperidine or indirectly from 2- (aminomethyl] pyridine. is reacted by heating in an unreactive solvent such as glyme, benzene, toluene or diethyl ether (preferably glyme) Alternatively, 2-aminomethylpyridine may be reacted with the acid chloride product of step (3) (d) in the presence of an inert solvent such as toluene or benzene This mixture is heated at reflux in the presence of an acid acceptor (eg a tertiary amine such as triethylamine). The adduct obtained from the reaction between a 2- (aminomethyl) pyridine and either compound V or VII is reduced to the desired product VIII by catalytic hydrogenation in the presence of platinum oxide or (preferably) platinum on carbon.The solvent used for this reaction is methanol or a lower alkanoic acid, such as (and f acetic acid and the preferred temperature range is 15-30 ° C. When acetic acid is used, the product obtained is flecainide acetate. The following examples illustrate the processes of the invention and the preparation of the intermediates and are not intended to limit the scope of the invention as described above.

EXAMPLE 1 Step (1) of the process: A = SO 2 QEB and X = OH To a mixture of 2.42 moles (334.4 g) of potassium carbonate, 2.2 moles (510.6 g) 2.2.2 -trifluoroethyltrifluoromethanesulfonate in 1.02 liters of acetone add a solution of 1.0 mol (110 g) of hydroquinone in 1.1 liters of acetone, slowly and over a period of 2 hours. The reaction mixture is then heated under reflux for 24 hours. , evaporated and 2 liters of chloroform and 2 liters of water are added to the residue. The chloroform layer is separated, the aqueous layer is washed twice with 1 liter of chloroform and the combined chloroform solution is washed with 1 liter of water.

The chloroform solution is dried over magnesium sulfate and then concentrated in vacuo. The hexane is added to the residue and the solid product is collected by ~ 15 20 25 30 ~ 35 "n: T \ L! e.g.), _) \ C.) 9 filtration and washed with hexane. Additional materials are collected from the concentrated residues. A yield of 88%, 241 g of 1,4-bis (2,2,2-trifluoroethoxy) benzene, m.p. 75-77 ° C, is obtained.

EXAMPLE 2 Step (1): A = Na and X = Br To 0.20 mol (9.69) of 50% sodium hydride in 40 ml of N, N-dimethylformamide is added 40 ml of 2,2,2-trifluoroethanol followed by 0.034 mol (8.0 g) 1,4-dibromobenzene and 0.006 mol (1.0 g) of copper (I) iodide. The mixture is heated at its reflux temperature for 4 hours, then cooled to 25 ° C and filtered. The residue is washed with N, N-dimethylformamide. The solution is then poured into water and the precipitate is separated by filtration. The product is dissolved in diethyl ether and filtered and the filtrate solution is evaporated to give a solid residue which is washed with hexane and dried. The product is 7.3 g (80%) of 1,4-bis- (2,2,2-trifluoroethoxy) benzene, mp 77-7900.

The reaction is repeated as follows, varying the conditions and proportions between the constituents and using copper (II) bromide as catalyst: to a mixture of 4.8 g of sodium hydride in 40 ml of N, N- -dimethylformamide is added 20 ml (27 , 4 g) 2,2,2-trifluoroethanol. To this mixture are added 0.034 moles (8.0 g) of 1,4-dibromobenzene and 1.0 g of copper (II) bromide. The reaction mixture is heated at 100 DEG C. for 2 hours, then quenched with ice water. Acidification with hydrochloric acid and filtration gives 9.2 g (99%) of white solid 1,4-bis (2,2,2) -trifluoroethoxy) benzene. The structure is confirmed by infrared spectral analysis.

EXAMPLE 3 Step (2) Using Acetic Anhydride as Acetylating Agent To a mixture of 2.43 moles (324 g) of aluminum chloride in 648 ml of dichloromethane is added a solution of 0.88 moles of 465 ml. (274 g) 1,4-bis (2,2,2-trifluoroethoxy) benzene and 0.97 mol (92 ml) of acetic anhydride in 880 ml of dichloromethane for a period of 3 hours while maintaining the temperature above 0 ° C.

The reaction mixture is then warmed to its reflux temperature and stirred at reflux for 5 hours. The course of the reaction is monitored by thin layer chromatography. The reaction mixture is concentrated in an ice bath and ice and 10% hydrochloric acid is added slowly to decompose the aluminum chloride complex. The temperature of the reaction mixture must not exceed 25 ° C. The organic phase is separated and washed once with 2 liters of 10% hydrochloric acid and then with 2 liters of water. the aqueous phase is extracted with the combined several liters of dichloromethane.

The organic phase is dried over magnesium sulphate and then evaporated to give a moist residue. The hexane is added to the residue and the resulting solid is collected by filtration and washed with hexane. After drying, 250 g of light yellow crystalline 2,5-bis (2,2,2-trifluoroethoxy) acetophenone are obtained.

The yield is so%, mp is 84 -6 ° C. IN EXAMPLE 4 An Enlargement of the Experiment of Example 3 To a mixture of 4367 g (32.75 moles) of aluminum chloride and 8.8 liters of chloromethane at 0 ° C was gradually added a solution of 3267 g of 1,4-bis ( 2,2,2-trifluoroethoxy) -benzene and 1.399 kg (1.3.7 mol) of acetic anhydride in 1.3 liters of dichloromethane. The reaction temperature is maintained at 5-10 ° C while the mixture is stirred for about 16 hours. The reaction mixture is then warmed to its reflux temperature and kept under reflux for 4 hours. The reaction mixture is then acidified with 8.76 kg of 10% hydrochloric acid.

Ice is added to the mixture to keep the temperature below 20 ° C. The organic layer is separated and the aqueous layers are extracted several times with dichloromethane.

The organic layers are dried and then evaporated to give a residue which is triturated with hexane to give a yellow solid product. Two product cycles are obtained, giving a total yield of 3,088 kg of 2,5-bis- (2,2,2-trifluoroethoxy) acetophenone, mp 84-8800, yield 82%.

EXAMPLE 5 Step (2) using acetyl chloride as acetylating agent To a mixture of 0.022 mol (2.8 g) of aluminum chloride and 100 ml of 1,2-dichloroethane is added dropwise at 2 ° C a solution of (5.6 g) 1,4-bie (2,2,2-trifluoroethoxy) benzene and 0.022 mol (1.7 g) of acetyl chloride in 20 ml of 1,2-dichloroethane. After stirring for 4 hours, the reaction mixture is washed with ice water and hydrogen chloride and the organic layer is dried. Evaporation gives a residue which is recrystallized from hexane to give 4.1 g (71%) of light yellow needles of 2,5-bis (2,2,2-trifluoroethoxy) acetophenone (which is varied by infrared spectral analysis).

EXAMPLE 6 Step (3) (a) A mixture of 0.25 mol (79.1 g) of 2,5-bis (2,2,2-trifluoroethoxy) acetophenone in 150 ml of acetic acid is heated to 50 ° C. Chlorine gas is bubbled into the solution and the temperature gradually increases to 55 ° C. The chlorine addition rate is adjusted to maintain the temperature at 55-60 ° C. After about 75 minutes, the temperature begins to drop (indicating that no chlorination is taking place). The total amount of chlorine added is 35.5 g. The resulting product is 2,5-b1e- (2,2,2-trifluoroethoxy) a, O-dichloroacetophenone.

EXAMPLE 7 Step (3) (b) To the product of the previous example (without isolation or purification) is added 0.35 mol (28.7 g) of sodium acetate. The temperature rises to about 80 ° C and the solution 260 èëš 260 10 15 20 25 30 »35 12 is heated to 85 ° C. The chlorine additive is resumed and the temperature increases to 10 ° C. After about 20 minutes, the theoretical amount of chlorine has been taken up and the mixture is kept in a mixture of ice and water. The precipitate which forms is collected by filtration, washed with water, dissolved in dichloromethane and dried. Evaporation gives a residue which is triturated with hexane to give a white solid.

A yield of 94 g (90%) of 2,5-bis (2,2,2-trifluoroethoxy) -α, α, α-trichloroacetophenone, mp 45-48 ° C, is obtained.

EXAMPLE 8 "i 'Step (3) lc) To a solution of 7.3 mol (292 g) of sodium hydroxide in 600 ml of water is added ice to bring the total volume to 1.75 liters. Chlorine gas is allowed to pass into the solution while the temperature kept below 10 ° C until neutral to litmus and 2.19 mol (87.6 g) of sodium hydroxide, dissolved in 200 ml of water, are added.

The combined solution is heated to 50 ° C and 0.73 mol (230 g) of 2,5-bis (2,2,2-trifluoroethoxy) acetophenone is added slowly. The reaction mixture is stirred while heating until an exotherm begins at about 75 ° C and is then maintained at about 80 ° C by cooling. The mixture is stirred for about 16 hours at about 80-90 ° C, while the degree of reaction is measured by thin layer chromatography. the excess hypochlorite is then destroyed by adding 75 g of sodium hydrogen sulphite in 250 ml of water and the mixture is cooled to about 25 ° C and carefully acidified with 10% hydrochloric acid. The light yellow solid product is collected by filtration, washed with water and dried.

A 94.5% yield of 2,5-bis (2,2,2-trifluoroethoxy) benzoic acid, mp 120-122 ° C, is obtained.

To a solution of 0.688 mol (219 g) of 2,5-bis- (2,2,2- "-trifluoroethoxy) benzoic acid in 657 ml of benzene is added 1.376M 10 15 20 25 30 35 13 (100 ml) thionyl chloride slowly for 1 h while heating to about 60 ° C. The mixture is then heated under reflux for about 8 hours and then evaporated to give the desired product, 2,5-bis- (2,2,2-trifluoroethoxy) benzoic acid chloride, as a residue. The structure is verified by infrared spectral analysis.

EXAMPLE 10 Step (4) carried out in two reactions starting from intermediate V To a solution of 0.05 mol (2.1, g) of 2,5-bisê (2,2,2-trifluoroethoxy) -a, a, a -trichloroacetophenone in 60 ml of toluene is added dropwise a solution of 0.055 mol (6.0 g) of 2-aminomethylpyridine in 50 ml of cyclohexane and 10 ml of toluene. The reaction is exothermic and a precipitate forms immediately.

Additional toluene and cyclohexane are added to give a mixing consistency that allows stirring and stirring is continued for 2 hours at about 25 ° C. The solid is then separated by filtration, washed with a mixture of toluene and cyclohexane and dried to give a white solid. The product is 2,5-bis (2,2,2-trifluoroethoxy) -N- (2-pyridylmethyl) benzamide, mp 104-106 ° C, 17.8 g, 89% yield.

A mixture of 0.33 mol (134.7 g) of 2,5-bis (2,2,2-trifluoroethoxy) -N- (2-pyridylmethyl) benzamide, 1.347 liters of glacial acetic acid and 13.5 g of 5% platinum on carbon is reduced in a Parr apparatus at a pressure of 13.6 kp hydrogen at room temperature. The reaction is complete in 6-7 hours. The reaction mixture is filtered and the catalyst is washed with isopropyl alcohol. The solution and the washing liquids are evaporated to give a residue. Hexane is added to the residue and the resulting white solid is collected and recrystallized from a mixture of acetone and hexane. A 71% yield of 2,5-bis (2,2,2-trifluoroethoxy) -N- (2-piperidylmethyl) benzamide acetate, mp 150-125 ° C, is obtained. By concentrating the remaining liquid, an additional -3 2650 p is obtained.

(JN 14 more 18% product as a second product round with a melting point of 148-150 ° C.

EXAMPLE 11 Step (4) carried out in a single reaction starting from the intermediate V To a solution of 0.01 mol (4.19 g) 2,5-bis- - (2,2,2-trifluoroethoxy) -a, a , c-trichloroacetophenone in 50 ml of isopropyl alcohol is added 0.01 mol (1.2 g) of 2-aminomethylpiperidine. The mixture gradually solidifies over a period of 10 minutes. The mixture is allowed to settle for about 16 hours, after which 0.01 M acetic acid and 5 ml of isopropyl alcohol are added and the solution is heated to dissolve all the solid.

On cooling, 3.0 g of white solid are obtained. The filtrate is evaporated and the residue is recrystallized from isopropyl alcohol to give additional product as a white solid. The product is 2,5-bis- (2,2,2-trifluoroethoxy) - -N- (2-piperidylmethyl) benzamide acetate according to its infrared and nuclear magnetic resonance spectra.

Example 12 'Step (4) carried out in two reactions starting from intermediate VII To a mixture of 0.77 mol (83.3 g) of 2-aminomethylpyridine, 0.77 mol (10.7.7 ml) of triethylamine and 300 ml of benzene, add 0.70 mol (236 g) of 2,5-bis- (2,2,2-trifluoroethoxy) benzoic acid chloride in 472 ml of benzene over a period of 1 hour.

The reaction mixture is stirred for about 16 hours at 25 ° C, kept under reflux for 1 hour and then washed twice with 2 liters of water. The aqueous phase is washed with 2 liters of benzene and the combined organic phases are dried over magnesium sulphate, after which they are evaporated in vacuo.

Recrystallization from a mixture of benzene and hexane gives 240 g, 86%, off-white 2,5-bis (2,2,2-trifluoroethoxy) -N- (2-pyrimylmethyl) benzamia, mp 100-120 ° C.

A mixture of 0.33 mol (134.7 g) of 2,5-bis (2,2,2-trifluoroethoxy) -N- (2-pyridylmethyl) benzamide, 1.347 liters of glacial acetic acid and 13.5 g of 5% platinum on carbon is reduced in 10 fa. \ __ | \ LN TJ - h CD 15 a Parr apparatus at a pressure of about 4.54 kp hydrogen at room temperature. The reaction is complete in 6-7 hours.

The reaction mixture is filtered and the catalyst is washed with isopropyl alcohol. The solution and the washing liquids are evaporated to give a residue. Hexane is added to the residue and the resulting white solid is collected and recrystallized from a mixture of acetone and hexane. A 71% yield of 2,5-bis (2,2,2- -trifluoroethoxy) -N- (2-piperidylmethyl) benzamide acetate, mp 150-125 ° C, is obtained. By concentrating the remaining liquid, an additional 18% of product is obtained as a second batch of products with a melting point of 148-150 ° C.

Claims (1)

A63 10 260 l6 CLAIMS Acetophenone of the formula II cr ca o CB ocH2cF3 wherein B is -CH3. fl